title: Loss of intestinal core 1-derived O-glycans causes spontaneous colitis in mice.
abstract: Mucin-type O-linked oligosaccharides (O-glycans) are primary components of the intestinal mucins that form the mucus gel layer overlying the gut epithelium. Impaired expression of intestinal O-glycans has been observed in patients with ulcerative colitis (UC), but its role in the etiology of this disease is unknown. Here, we report that mice with intestinal epithelial cell-specific deficiency of core 1-derived O-glycans, the predominant form of O-glycans, developed spontaneous colitis that resembled human UC, including massive myeloid infiltrates and crypt abscesses. The colitis manifested in these mice was also characterized by TNF-producing myeloid infiltrates in colon mucosa in the absence of lymphocytes, supporting an essential role for myeloid cells in colitis initiation. Furthermore, induced deletion of intestinal core 1-derived O-glycans caused spontaneous colitis in adult mice. These data indicate a causal role for the loss of core 1-derived O-glycans in colitis. Finally, we detected a biosynthetic intermediate typically exposed in the absence of core 1 O-glycan, Tn antigen, in the colon epithelium of a subset of UC patients. Somatic mutations in the X-linked gene that encodes core 1 β1,3-galactosyltransferase-specific chaperone 1 (C1GALT1C1, also known as Cosmc), which is essential for core 1 O-glycosylation, were found in Tn-positive epithelia. These data suggest what we believe to be a new molecular mechanism for the pathogenesis of UC.
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Fu
authors.forename: Bo
authors.initials: B
authors.lastname: Wei
authors.forename: Tao
authors.initials: T
authors.lastname: Wen
authors.forename: Malin E V
authors.initials: ME
authors.lastname: Johansson
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Liu
authors.forename: Emily
authors.initials: E
authors.lastname: Bradford
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Thomsson
authors.forename: Samuel
authors.initials: S
authors.lastname: McGee
authors.forename: Lilah
authors.initials: L
authors.lastname: Mansour
authors.forename: Maomeng
authors.initials: M
authors.lastname: Tong
authors.forename: J Michael
authors.initials: JM
authors.lastname: McDaniel
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sferra
authors.forename: Jerrold R
authors.initials: JR
authors.lastname: Turner
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.forename: Gunnar C
authors.initials: GC
authors.lastname: Hansson
authors.forename: Jonathan
authors.initials: J
authors.lastname: Braun
authors.forename: Lijun
authors.initials: L
authors.lastname: Xia
mesh_terms: D000818:Animals; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000378:metabolism; D001483:Base Sequence; D003092:Colitis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D005700:Galactosyltransferases / Q000172:deficiency / Q000235:genetics; D006801:Humans; D007413:Intestinal Mucosa / Q000002:abnormalities / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011134:Polysaccharides / Q000172:deficiency*
chemical_list: D015295:Antigens, Tumor-Associated, Carbohydrate; C505369:C1GALT1C1 protein, human; C514310:Cosmc protein, mouse; D017931:DNA Primers; D018832:Molecular Chaperones; D011134:Polysaccharides; C040286:Tn antigen; C515597:C1galt1 protein, mouse; D005700:Galactosyltransferases